Bifeprunox mesylate maintenance dose compositions and methods for using the same

ABSTRACT

The present disclosure provides novel pharmaceutical dosage forms such as a maintenance treatment dose and methods for making the same, and methods for using said compounds and maintenance treatment doses to treat and prevent diseases and/or disorders.

This application is a continuation-in-part of U.S. application Ser. No.11/354,652, filed on Feb. 16, 2006, which claims the benefit of priorityof U.S. Provisional Application No. 60/654,149, filed on Feb. 18, 2005,both of which are incorporated herein by reference in their entirety.

The present disclosure relates to stable polymorphic forms of thecompound7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate, methods for the preparation of such polymorphicforms, pharmaceutical dosage forms such as a maintenance treatment dosecomprising said polymorphic forms, and methods for using the maintenancetreatment dose for the treatment of various disorders such as, CNSdisorders.

The mesylate salt of the compound7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate (INNM bifeprunox mesylate) has the formula

The hydrochloric acid salt of this compound(7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone(bifeprunox) is described and claimed in WO97/36893 and themonomethanesulfonate salt is described and claimed in WO02/066449. Inthe second of these patent publications the direct formation of themonomethanesulfonate salt by the reaction between the reactive mesylateester of N,N,N-bis(2-ethanol)-m-phenylbenzyl amine and7-amino-2(3H)-benzoxazolone is disclosed.

It has been discovered that by the method described in WO02/066449bifeprunox mesylate is normally obtained as a crude product (meltingrange indicated in WO02/066449 as 263-275° C.) in a polymorphic formfurther indicated in this application as polymorph δ (delta). Uponfurther purification, the product is obtained in two different crystalmodifications or a mixture of these two modifications. The first of thetwo modifications is the already mentioned polymorph δ (delta) and has amelting point in pure form of 265° C. The second modification is furtherindicated as polymorph γ (gamma). When the γ polymorph is predominantlyobtained, it is in almost all cases obtained in a mixture of saidpolymorph with polymorph δ, the mixture having a melting point ofapproximately 273° C.

During further investigations it appeared that polymorphs γ and δ aremetastable, and therefore may have drawbacks when used in apharmaceutical formulation. The unpredictable formation of one of thetwo polymorphs γ and δ or a mixture thereof is also undesirable. Itwould be desirable, therefore, to provide a stable crystalline form of7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate for pharmaceutical use which can be consistentlyproduced.

It has surprisingly been found that7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate also has another crystalline polymorphic form(referred to below as polymorph α (alpha)) which does not have thedisadvantages of the aforementioned polymorphs. This crystalline form ofbifeprunox mesylate is more thermodynamically stable. Polymorphic form αdoes not undergo conversion, even at high atmospheric humidity or highertemperature. Furthermore this crystalline form crystallizes in the formof large crystals which can be easily filtrated and have a high purity.Therefore this polymorph α is particularly suitable for the formulationof bifeprunox mesylate in a solid form, if desired after particle sizereduction.

In various embodiments, the present disclosure provides the polymorphicα form of bifeprunox mesylate at various levels of purity. In anotherembodiment, the present disclosure provides pharmaceutical dosage formssuch as a maintenance treatment dose comprising the polymorphic α formof bifeprunox mesylate. In yet another embodiment, the presentdisclosure provides methods for using the maintenance treatment dose fortreatment or prevention of various diseases and disorders. Theseembodiments, while providing some general overview of variousembodiments of the present disclosure, are not intended to limit thescope of the present disclosure in any manner.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an XRPD pattern of polymorphic form α of bifeprunoxmesylate.

FIG. 2 shows a DSC trace of polymorphic form α of bifeprunox mesylate.

FIG. 3 shows an IR (ATR) spectrum of polymorphic form α of bifeprunoxmesylate.

FIG. 4 shows a ¹³C solid state NMR spectrum of polymorphic form α ofbifeprunox mesylate.

FIG. 5 shows configuration of polymorphic form α of bifeprunox mesylatederived from X-ray crystallography.

FIG. 6 shows an XRPD pattern of polymorphic form γ of bifeprunoxmesylate.

FIG. 7 shows a DSC trace of polymorphic form γ of bifeprunox mesylate.

FIG. 8 shows an IR (ATR) spectrum of polymorphic form γ of bifeprunoxmesylate.

FIG. 9 shows a ¹³C solid state NMR spectrum of polymorphic form γ ofbifeprunox mesylate.

FIG. 10 shows configuration of polymorphic form γ of bifeprunox mesylatederived from X-ray crystallography.

FIG. 11 shows an XRPD pattern of polymorphic form δ of bifeprunoxmesylate.

FIG. 12 shows a DSC trace of polymorphic form δ of bifeprunox mesylate.

FIG. 13 shows an IR (ATR) spectrum of polymorphic form δ of bifeprunoxmesylate.

FIG. 14 shows a ¹³C solid state NMR spectrum of polymorphic form δ ofbifeprunox mesylate.

FIG. 15 shows configuration of polymorphic form δ of bifeprunox mesylatederived from X-ray crystallography.

FIG. 16 shows the plasma concentration-time profile followingmultiple-dose administration of bifeprunox at 40 mg/day in healthysubjects (n=16).

FIG. 17 shows bifeprunox plasma concentration-time profiles with andwithout (A) ketoconazole, (B) fluconazole, (C) paroxetine, and (D)carbamazepine.

FIG. 18 shows a mean prothrombin time profile as a function of study day(i.e., the day after treatment) with warfarin alone and in combinationwith bifeprunox (40 mg/day)

In one embodiment, the crystalline polymorphic form of bifeprunoxmesylate according to the present disclosure is defined by at least oneof the following physicochemical parameters:

X-Ray diffraction patterns (Table 1 and FIG. 1);

The melting point of polymorphic form α is 277° C. (DSC heating rate 10K/min) (see DSC thermogram, FIG. 2);

IR spectrum (Table 2 and FIG. 3), wherein the characteristic IRabsorption bands of form α of bifeprunox mesylate which can be used todistinguish this form from forms γ and δ are given in Table 2a;

Solid state ¹³C-NMR spectrum (Table 3 and FIG. 4), wherein thecharacteristic ¹³C-NMR shifts of form α of bifeprunox mesylate which canbe used to distinguish this form from forms γ and δ are given in Table3a;

Single crystal X-ray diffraction (Tables 4 and 5 and FIG. 5).

Table 1 shows characteristic X-ray powder diffractions (XRPD) of formsα, γ and δ of bifeprunox mesylate. FIG. 1 provides a representative XRPDpattern of polymorphic form α of bifeprunox mesylate.

TABLE 1 Characteristic reflexes (expressed in degree of diffractionangle 2θ Form at room temperature) α 7.0, 9.3, 10.0, 12.5, 15.4, 16.7,17.2, 17.4, 17.7, 18.7, 21.3, 22.2, 25.2, 27.2, 28.3, 28.8, 30.1 γ 10.4,11.4, 11.7, 14.1, 15.1, 21.0, 26.9 δ 6.4, 10.2, 12.1, 16.4, 16.8, 19.3,19.7, 20.6, 24.1, 26.6

Table 2 shows characteristic IR absorption bands of forms α, γ and δ ofbifeprunox mesylate. FIG. 2 provides a representative IR spectrum ofpolymorphic form α of bifeprunox mesylate.

TABLE 2 Form Characteristic IR absorption bands (expressed in cm⁻¹) α1764, 1636, 1284, 1217, 809, 795, 746, 694, 663, 509 γ 1777, 1279, 1258,1210, 1124, 800, 764, 749, 627, 518 δ 1865, 1769, 1434, 1282, 1253,1212, 1126, 935, 767, 751

Table 2a also shows important IR absorption bands of forms α, γ and δ ofbifeprunox mesylate which can be used to distinguish the three forms.

TABLE 2a Form Characteristic IR absorption bands (expressed in cm ⁻¹) α1764, 1217, 795, 746, 694 γ 1777, 1210, 764, 749, 518 δ 1769, 1212, 935,767, 751

Table 3 shows characteristic ¹³C solid state NMR chemical shifts informs α, γ and δ of bifeprunox mesylate. FIG. 3 provides arepresentative

¹³C solid state NMR spectrum of polymorphic form α of bifeprunoxmesylate.

TABLE 3 Characteristic chemical shift (expressed in ppm relative to Formglycine (δ_(c) = 176.03 for the C═O resonance) α 40.4, 48.7, 50.3, 56.5,106.8, 110.7, 124.9, 126.9, 127.8, 129.2, 130.8, 134.2, 137.7, 141.6,and *153.8. γ 38.2, *44.3, *45.9, 50.1, 54.5, 59.4, 103.5, 109.3, 125.3,127.9, 128.9, 131.1, 133.2, 134.5, 141.2, 143.2 and *153.7 δ 39.1,*44.3, *46.3, 49.3, 53.4, 58.8, 104.6, 110.4, 124.6, 127.0, 128.5,129.7, 130.5, 134.4, 141.5, 143.5, and *154.7 *denotes carbon resonanceswhich show typical asymmetric residual quadrupolar splittings. Chemicalshift are given for the high-field resonance maximum.

Table 3a also shows important ¹³C solid state NMR chemical shifts bandsof forms α, γ and δ of bifeprunox mesylate which can be used todistinguish the three forms.

TABLE 3a Characteristic chemical shift (expressed in ppm relative toForm glycine (δ_(c) = 176.03 for the C═O resonance) α 40.4, 48.7, 56.5,106.8 and 137.7 γ 38.2, 54.5, 103.5, 109.3 and 133.2 δ 39.1, 49.3, 53.4,58.8 and 104.6

Table 4 shows relevant Single Crystal X-ray Diffraction data collectionparameters for the crystal structure determination of forms α, γ and δof bifeprunox mesylate.

TABLE 4 Alpha (α) Gamma (γ) Delta (δ) Temperature (K) 150 133 150Wavelength (Å) 0.71073¹ 0.71073 0.71073 Crystal size 0.10 × 0.15 × 0.270.24 × .13 × 0.07 0.10 × 0.15 × 0.35 (mm × mm × mm) Crystal systemtriclinic monoclinic triclinic Space group P-1 P2₁/c P-1 Z 2 4 2 Unitcell dimensions; A (Å) 9.823 9.0975 9.1832 B (Å) 10.737 15.269 9.3963 C(Å) 12.690 17.128 14.106 α (°) 98.553 90 76.968 β (°) 93.749 100.69483.809 Γ (°) 116.097 90 89.157 Calculated density (g cm⁻³) 1.481 1.3681.3556 Completeness of data (%) 100.0 100.0 99.8 Total number ofreflections 27105 23759 27207 Number of unique 5355 5809 4149reflections Nr. Of refined parameters 314 316 314

Table 5 shows atomic coordinates (×10⁴) and equivalent isotropicdisplacement parameters (Å²×10³) of crystal structure of form α ofbifeprunox mesylate. U(eq) is defined as one third of the trace of theorthogonalized U_(ij) tensor.

TABLE 5 x y z U(eq) O1 3471.7(11) 3848.0(10) 2910.8(8) 26.4(3) O22785.8(13) 1499.8(11) 2541.1(10) 38.1(4) N1 5215.5(15) 3175.4(14)3398.0(11) 29.3(4) N2 3880.6(13) 6773.4(13) 3211.0(10) 24.6(4) N31702.0(14) 7879.1(13) 3177.7(11) 24.9(4) C1 3755.9(18) 2687.4(17)2914.9(13) 28.6(5) C2 4801.7(16) 5042.8(16) 3421.0(12) 23.7(4) C35896.6(17) 4637.6(16) 3727.8(12) 25.8(5) C4 7334.0(17) 5622.3(17)4265.8(12) 28.3(5) C5 7587.8(18) 7016.7(18) 4470.3(12) 30.7(5) C66489.3(17) 7425.7(17) 4145.1(12) 28.2(5) C7 5035.3(17) 6432.4(16)3594.8(12) 24.3(4) C8 4371.2(18) 8285.6(16) 3280.4(14) 29.8(5) C93141.4(17) 8515.3(17) 2694.6(13) 29.2(5) C10 1196.3(17) 6328.4(15)3094.7(13) 25.8(5) C11 2450.2(16) 6106.0(16) 3661.4(12) 25.9(5) C12 465.7(18) 8238.1(17) 2763.9(13) 29.1(5) C13 −273.5(18) 7526.6(18)1622.4(13) 30.9(5) C14  166(2)  8245(2) 780.4(15) 46.7(7) C15  −586(2) 7574(3) −256.4(16) 57.6(8) C16 −1734(2)   6194(2) −466.0(15) 49.2(7)C17 −2206.8(19)  5456.1(19) 362.2(13) 34.9(6) C18 −1474.4(18) 6157.3(18) 1409.5(13) 30.8(5) C19 −3495(2)  4003.7(19) 170.3(13) 37.1(6)C20 −4751(2)   3585(2) −623.3(14) 43.7(6) C21 −5976(2)   2260(2)−766.8(17) 54.6(7) C22 −5989(2)   1318(2) −129.3(18) 58.2(8) C23−4750(3)   1709(2) 655.0(17) 54.6(7) C24 −3520(2)   3039(2) 804.2(15)45.3(6) S1 8220.4(4)  1865.1(4)  3801.4(3) 26.8(1) O3 6650.8(13)1454.8(12) 3355.9(10) 40.2(4) O4 8282.1(15) 1197.6(13) 4711.2(9) 42.6(4)O5 9171.5(14) 3369.6(12) 4040.9(11) 48.7(4) C25  8951(2)  1114(2)2801.2(15) 51.0(7) ¹(Mo Kα radiation)

Table 6 shows atomic coordinates (×10⁴) and equivalent isotropicdisplacement parameters (Å²×10³) of crystal structure of form γ ofbifeprunox mesylate. U(eq) is defined as one third of the trace of theorthogonalized U_(ij) tensor.

TABLE 6 x y z U(eq) O(1) 6610.7(11) 756.7(7) 6306.4(6) 26.6(2) O(2)9117.5(12) 552.8(8) 6513.4(8) 40.3(3) C(2) 7882.4(17) 240.9(11)6352.9(10) 29.1(4) N(3) 7439.1(14) −598.9(9) 6206.3(8) 27.4(3) C(3A)5878.6(17) −646.4(10) 6063.5(9) 24.5(3) C(4) 4896.5(18) −1346.6(11)5948.7(9) 31.7(4) C(5) 3392.7(19) −1133.4(11) 5866.9(10) 35.5(4) C(6)2894.2(18) −281.1(11) 5915.0(9) 32.3(4) C(7) 3884.2(17) 428.8(10)6069.0(9) 26.2(3) C(7A) 5382.3(16) 199.5(10) 6119.9(8) 23.7(3) N(1′)3465.6(14) 1286.2(8) 6230.9(8) 28.4(3) C(2′) 1876.4(18) 1434.5(11)6215.9(11) 35.7(4) C(3′) 1661.2(18) 2283.3(11) 6630.8(11) 36.5(4) N(4′)2322.4(14) 3039.8(9) 6262.9(8) 28.0(3) C(5′) 3942.4(17) 2861.2(11)6265.4(10) 30.0(4) C(6′) 4103.6(17) 2010.2(10) 5840.3(9) 27.2(3) C(10) 2051(2) 3884.9(11) 6667.0(10) 35.6(4) C(11) 2788.0(18) 4658.9(11)6354.3(9) 30.7(4) C(12) 2314.0(17) 4949.2(10) 5577.8(9) 27.8(4) C(13)3015.0(17) 5646.9(10) 5277.0(9) 26.8(3) C(14) 4183.8(18) 6072.6(11)5781.3(10) 33.7(4) C(15)  4644(2) 5795.6(12) 6554.8(11) 40.5(4) C(16)3964.4(19) 5086.4(12) 6836.9(10) 38.5(4) C(21) 2576.4(16) 5917.7(10)4432.7(9) 25.3(3) C(22) 2266.8(17) 5286.3(11) 3836.1(9) 29.8(4) C(23)1921.6(19) 5532.9(11) 3043.3(10) 35.0(4) C(24) 1900.5(18) 6409.3(11)2833.0(10) 33.3(4) C(25) 2200.7(17) 7041.3(11) 3419.1(10) 31.8(4) C(26)2519.2(17) 6797.7(10) 4209.4(10) 29.3(4) S 9163.9(4)  −2786.7(3)5975.1(2) 28.4(1) O(3) 9584.0(13) −1870.9(7) 6067.6(8) 39.5(3) O(4)7714.0(13) −2961.4(8) 6156.0(8) 48.0(4) O(5) 9327.4(15) −3123.8(9)5197.7(7) 50.7(4) C(1M) 10484.0(18)  −3388.0(11) 6647.3(9) 33.1(4)

Table 7 shows atomic coordinates (×10⁴) and equivalent isotropicdisplacement parameters (Å²×10³) of crystal structure of form δ ofbifeprunox mesylate. U(eq) is defined as one third of the trace of theorthogonalized U_(ij) tensor.

TABLE 7 x y z U(eq) O1 4353.9(14)  2151.8(14)  9.8(9) 31.7(5) O22013.8(15)  1799.9(16)  −260.0(11) 41.7(6) N1 3473.0(19)  3697(2)−1220.7(13) 33.0(6) N2 7357.2(17)  2103.5(19)  550.2(12) 32.1(6) N38449.3(17)   325.4(19) 2265.2(12) 30.5(6) C1 3130(2) 2515(2) −491.7(15)31.6(8) C2 5441(2) 3184(2) −431.7(14) 27.6(7) C3 4912(2) 4146(2)−1202.7(15) 29.5(7) C4 5792(2) 5233(2) −1804.5(16) 38.0(8) C5 7222(2)5295(2) −1576.5(17) 40.4(8) C6 7745(2) 4328(2) −796.9(16) 35.7(8) C76862(2) 3203(2) −190.9(15) 29.9(7) C8 8926(2) 2107(2) 662.0(15) 36.3(8)C9 9346(2)  659(2) 1284.5(15) 36.0(7) C10 6854(2)  364(2) 2127.3(15)33.3(7) C11 6484(2) 1826(2) 1508.8(14) 34.0(7) C12 8900(2) −1091(2) 2896.8(15) 35.7(8) C13 7978(2) −1468(2)  3868.2(15) 32.6(7) C14 6997(2)−2644(2)  4086.9(17) 40.5(8) C15 6109(2) −2941(2)  4966.4(17) 42.7(8)C16 6171(2) −2068(2)  5624.7(16) 39.1(8) C17 7146(2) −888(2) 5437.5(15)32.1(7) C18 8054(2) −613(2) 4552.0(15) 32.2(7) C19 7171(2)  74(2)6137.9(15) 31.4(7) C20 7068(2) −494(2) 7144.3(15) 34.8(7) C21 7028(2) 422(3) 7794.2(16) 38.2(8) C22 7099(2) 1919(3) 7448.1(16) 39.7(8) C237201(2) 2497(2) 6453.5(16) 41.0(8) C24 7234(2) 1589(2) 5798.4(16)37.9(8) S1 8731.8(6)  3909.1(6)  3076.9(4) 33.3(2) O3 9471.7(16) 2602.8(16)  2887.4(12) 50.3(6) O4 7233.7(16)  3640.6(18)  3484.5(11)50.4(6) O5 8877.7(16)  5117.0(17)  2228.8(11) 47.6(5) C25 9712(3)4404(3) 3958.1(17) 48.8(9)

The polymorphic form α differs substantially from the forms γ and δ inits physicochemical parameters: DSC melting behavior, X-ray diffractionpattern, IR spectrum and solid state ¹³C-NMR spectrum. Thephysicochemical parameters of the forms γ and δ are given in Tables 1-4,6 and 7 and FIGS. 6-15.

In another embodiment, the present disclosure provides bifeprunoxmesylate in which at least about 50 percent by weight (wt. %), at leastabout 60 wt. %, at least about 70 wt. %, at least about 80 wt. %, atleast about 90 wt. %, or at least about 95 wt. % of the bifeprunoxmesylate is in the polymorphic α form. In other embodiment, suchembodiments are substantially devoid of any γ or δ polymorphic forms ofbifeprunox mesylate. In another embodiment, the bifeprunox mesylateprovided by the present disclosure comprises less than 10 wt. %, lessthan 5 wt. %, or less than 2.5 wt. % of the γ or δ polymorphic forms ofbifeprunox mesylate. In another embodiment, at least about 99 wt. % ofbifeprunox mesylate is in the polymorphic α form.

In one embodiment, the preparation of the polymorphic form α is carriedout by recrystallization from an organic solvent or a mixture of anorganic solvent with water, preferably a mixture of a (C₁-C₆) alcoholand water or a mixture of acetonitrile and water. In another embodiment,the solvent is a mixture is 2-propanol and water or a mixture ofacetonitrile and water. In another embodiment, the solvent is a mixtureof acetonitrile and water. The polymorphic form γ can be prepared bymaking the free base of bifeprunox directly followed by the addition ofmethane sulphonic acid and crystallization from methylethylketone.

The polymorphic form α and γ according to the present disclosure can beformulated into dosage forms in which the crystalline active substanceis present in the solid form by methods known in the art. Examples ofsaid dosage forms are (optionally coated) tablets, capsules, granularaerosols, suppositories and suspensions. Such dosage forms can beprepared by mixing the polymorphic form α or γ of the active substancewith inert pharmaceutically acceptable excipients and carriers.

In one embodiment, one to a small plurality (e.g. 1 to about 4) ofdosage units of a composition of the present disclosure comprise about0.05 to about 40 mg, about 0.75 to about 35 mg, about 0.1 to about 30 mgor about 0.125 to about 20 mg of bifeprunox mesylate (in α, δ, and/or γform) per dosage unit. Illustratively, such a dosage unit can comprise0.125 mg, 1 mg, 5 mg, 10 mg, or 20 mg of bifeprunox mesylate. In anotherembodiment of the present invention, the dosage units of the compositioncomprise about 20 mg to about 40 mg of bifeprunox mesylate, such as 20mg or 40 mg of bifeprunox mesylate.

Any of the dosage units of the present invention may comprise atreatment maintenance dose. For example, a maintenance treatment dosemay include about 20 mg or about 40 mg of bifeprunox mesylate. As usedherein, the term “maintenance treatment dose” refers to a target dose orfinal dose for treatment, which dose is reached after a titrationschedule during a period of time in which the strength or amount ofbifeprunox compound in each unit dosage increases incrementally overcertain time intervals. Moreover, the maintenance treatment dose may begiven to a patient over a long period of time, even chronically.Generally, the maintenance treatment dose is administered daily,however, other time intervals may also be considered.

Compositions of the present disclosure can comprise one or morepharmaceutical excipients. Non-limiting examples of suitable excipientsinclude suspending agents (for example, gums, xanthans, cellulosics andsugars), humectants (for example, sorbitol), solubilizers (for example,ethanol, water, PEG and propylene glycol), surfactants (for example,sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine),preservatives, antioxidants (for example, parabens, and vitamins E andC), anti-caking agents, coating agents, chelating agents (for example,EDTA), stabilizers, antimicrobial agents, antifungal or antibacterialagents (for example, parabens, chlorobutanol, phenol, sorbic acid),isotonic agents (for example, sugar, sodium chloride), thickening agents(for example, methyl cellulose), flavoring agents (for example,chocolate, thalmantin, aspartame, root beer or watermelon or otherflavorings stable at pH 7 to 9), anti-foaming agents (e.g., simethicone,Mylicon®), disintegrants, flow aids, lubricants, adjuvants, colorants,diluents, moistening agents, preservatives, carriers, binders (forexample, hydroxypropylmethylcellulose, polyvinyl pyrilodone, othercellulosic materials and starch), diluents (for example, lactose andother sugars, starch, dicalcium phosphate and cellulosic materials),disintegrating agents (for example, starch polymers and cellulosicmaterials), glidants and water insoluble or water soluble lubricants orlubricating agents.

One illustrative dosage form comprises, apart from the milled and sievedactive substance (bifeprunox as described herein), lactose monohydrate,microcrystalline cellulose, sodium starch glycolate (for example, typeA), sodium stearyl fumarate and optionally colloidal anhydrous silica.In one embodiment, lactose is present in an amount of about 20% to about90% by weight, about 70% to about 90% by weight, or about 75% to about85% by weight, based on the total weight of the tablet core.Microcrystalline cellulose is present in an amount of about 5% to about90% by weight, about 10% to about 15% by weight, or about 11% to about12% by weight, based on the total weight of the tablet core. Sodiumstarch glycolate (e.g. type A) is present in an amount of about 0.1% toabout 2.5% by weight, about 0.3% to about 0.7% by weight, or about 0.5%by weight, based on the total weight of the tablet core. Sodium stearylfumarate is present in an amount of about 0.1% to about 1.5% by weight,about 0.6% to about 1.3% by weight, or about 1.0% by weight, based onthe total weight of the tablet core. Colloidal anhydrous silica isoptionally added to the formulation in order to improve the flowproperties of the powder. If desired, colloidal anhydrous silica istypically present in an amount of about 0.05% to about 0.5% by weight orabout 0.4% by weight, based on the total weight of the tablet core. Theamount of optional coating is about 2.0% to about 5.0% by weight, about3.0% to about 4.0% by weight, or about 3.5% by weight, based on thetotal weight of the tablet core.

In another embodiment, the present disclosure relates to a method ofproducing the formulation described above, wherein the active substancehaving the polymorphic form α or γ according to the present disclosureis milled and subsequently using a suitable mixer (e.g. an orbital screwmixer (Nauta mixer) or a combination of a diffusion mixer (bin blender)with a rotating impeller mill (quadro co-mill)) with lactosemonohydrate, microcrystalline cellulose, sodium starch glycolate type A,sodium stearyl fumarate and optionally with colloidal anhydrous silica.The mixture is then pressed into tablets of the desired activeingredient strength. During tabletting any suitable pressure can beused, for example about 200 MPa to about 400 MPa, about 250 MPa to about350 MPa, or about 300 MPa. The dosage form is optionally coated with acolor and taste coating by spraying of a coating suspension onto thetablet core using any suitable coating equipment (e.g. a perforated pancoater or a fluidized bed coater).

Pharmaceutical compositions comprising the polymorphic form α and/or γaccording to the present disclosure can be administered to a subject,for example a human subject, in need thereof. Such compositions areuseful for, inter alia, the treatment of humans suffering from psychoticdisorders (e.g. schizophrenia) or Parkinson's disease.

In one embodiment of the present disclosure, upon oral administration ofa composition of the present invention to a human subject (or aplurality thereof), for example a fasted adult human subject, thesubject exhibits a plasma T_(max) (or a mean plasma T_(max) ifadministered to a plurality of human subjects) of bifeprunox withinabout 3 hours, within about 2.8 hours, within about 2.7 hours, withinabout 2.6 hours, within about 2.5 hours, within about 2.4 hours, withinabout 2.3 hours, within about 2.2 hours, within about 2.1 hours orwithin about 2 hours. In a further embodiment of the present invention,upon administration of a composition of the present disclosure to ahuman subject, the subject exhibits a plasma T_(max) ranging from 0.5hour to 8.0 hours, such as 1.5 hours or 2.0 hours. The term “T_(max)”refers to the time at which the maximum plasma concentration ofbifeprunox is attained following administration of bifeprunox mesylateto the subject.

In another embodiment of the present disclosure, upon oraladministration of a composition of the present invention to a humansubject (or a plurality thereof), for example a fasted adult humansubject, the subject exhibits a plasma C_(max) (or a mean C_(max) ifadministered to a plurality of human subjects) of bifeprunox of at leastabout 0.1 ng/ml, at least about 0.12 ng/ml, at least about 0.13 ng/ml,at least about 0.14 ng/ml, at least about 0.15 ng/ml, at least about0.16 ng/ml, at least about 0.17 ng/ml, at least about 0.18 ng/ml, atleast about 0.19 ng/ml, at least about 0.2 ng/ml, at least about 0.21ng/ml, at least about 0.22 ng/ml, at least about 0.23 ng/ml, at leastabout 0.24 ng/ml, at least about 0.25 ng/ml, at least about 0.26 ng/ml,at least about 0.27 ng/ml, or at least about 0.28 ng/ml. In a furtherembodiment of the present disclosure, upon administration of acomposition of the present invention to a human subject, the subjectexhibits a plasma C_(max) of at least about 62.1±38.2 ng/ml, such as aplasma C_(max) that ranges from about 23.9 ng/ml to about 100.3 ng/ml.The term “C_(max)” refers to the maximum plasma concentration ofbifeprunox.

In another embodiment of the present disclosure, upon oraladministration of a composition of the present invention to a humansubject (or a plurality thereof), for example a fasted adult humansubject, the subject exhibits a plasma AUC₀₋₂₄ (or a mean plasma AUC₀₋₂₄if administered to a plurality of human subjects) of bifeprunox of atleast about 0.9 hr·ng/ml, 1.0 hr·ng/ml, 1.1 hr·ng/ml, 1.2 hr·ng/ml, 1.3hr·ng/ml, or 1.4 hr·ng/ml. In a further embodiment, upon administrationof a composition of the present invention to a human subject, thesubject exhibits a plasma AUC₀₋₂₄ of bifeprunox ranging from about 100hr·ng/ml to about 900 hr·ng/ml, such as at least about 401.5±292.2hr·ng/ml or for example, the AUC₀₋₂₄ may range from about 109.3 hr·ng/mlto about 693.7 hr·ng/ml, and further for example, the plasma AUC₀₋₂₄ maybe about 381.5 hr·ng/ml or may be about 825.1 hr·ng/ml. The term“AUC₀₋₂₄” refers to the area under the plasma concentration versus timecurve for the twenty-four hour period after administration.

AUC is a common measure of the extent of bioavailability (relative) of apharmaceutically active agent provided by a particular route ofadministration (e.g., oral intravenous, buccal, etc.). As used herein,the term “bioavailability” refers to the amount of unchanged activeagent, e.g., bifeprunox, reaching the systemic circulation followingadministration by a particular route. In yet a further embodiment of thepresent invention, upon administration of a composition of the presentinvention to a human subject, the composition displays a bioavailabilityof at least 50%, such as at least about 54%. That bioavailability waspredicted by considering hepatic blood flow and oral clearance.

In another embodiment of the present disclosure, upon oraladministration of a composition of the present invention to a humansubject (or a plurality thereof), for example a fasted adult humansubject, the subject exhibits a steady-state elimination half life(t_(1/2)) following multiple dose administration of at least about14.4±5.3 hours, such as from about 9.1 hours to about 19.7 hours. Asused herein, the term “t_(1/2)” refers to the time required to changethe amount of active agent, e.g., bifeprunox, in the subject by one-halfduring elimination.

In yet a further embodiment of the present invention, upon oraladministration of a composition of the present invention to a humansubject (or plurality thereof), for example a fasted human subject, thesubject exhibits an apparent volume of distribution corrected by bodyweight ranging from about 7.9 V_(Zbw)/F to about 26.7 V_(Zbw)/F (L/kg),such as about 17.3 V_(Zbw)/F. Moreover, the subject may exhibit a weightnormalized clearance ranging from about 0.6 CL_(bw)/F to about 1.2CL_(bw)/F, such as 0.9 CL_(bw)/F (L/h/kg).

In still another embodiment, upon oral administration of a compositionof the present invention to a human subject (or a plurality thereof),for example a fasted adult human subject, the subject exhibits at leastone of:

A. A plasma T_(max) (or a mean T_(max) if administered to a plurality ofhuman subjects) of bifeprunox within about 0.5 to about 8 hours, withinabout 3 hours, within about 2.8 hours, within about 2.7 hours, withinabout 2.6 hours, within about 2.5 hours, within about 2.4 hours, withinabout 2.3 hours, within about 2.2 hours, within about 2.1 hours orwithin about 2 hours;

B. A plasma C_(max) (or a mean C_(max) if administered to a plurality ofhuman subjects) of bifeprunox of at least about 0.1 ng/ml, at leastabout 0.12 ng/ml, at least about 0.13 ng/ml, at least about 0.14 ng/ml,at least about 0.15 ng/ml, at least about 0.16 ng/ml, at least about0.17 ng/ml, at least about 0.18 ng/ml, at least about 0.19 ng/ml, atleast about 0.2 ng/ml, at least about 0.21 ng/ml, at least about 0.22ng/ml, at least about 0.23 ng/ml, at least about 0.24 ng/ml, at leastabout 0.25 ng/ml, at least about 0.26 ng/ml, at least about 0.27 ng/ml,at least about 0.28 ng/ml, or at least about 62.1±38.2 ng/ml; or

C. A plasma AUC₀₋₂₄ (or a mean AUC₀₋₂₄ if administered to a plurality ofhuman subjects) of bifeprunox of at least about 0.9 hr·ng/ml, 1.0hr·ng/ml, 1.1 hr·ng/ml, 1.2 hr·ng/ml, 1.3 hr·ng/ml, or 1.4 hr·ng/ml, orat least about 401.5±292.2 hr·ng/ml.

In yet another embodiment, the present invention provides for methodsfor treating at least one central nervous system (CNS) disorder in ahuman subject in need thereof, comprising administering to the subject apharmaceutical composition comprising an effective amount of bifeprunox,a crystalline polymorph of7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate, and at least one pharmaceutically acceptableexcipient, wherein the effective amount of bifeprunox comprises amaintenance treatment dose and following administration of an effectiveamount of the composition to the subject, the subject exhibits at leastone of:

(a) a plasma T_(max) from about 0.5 to about 8.0 hours;

(b) a plasma C_(max) of at least about 62.1±38.2 ng/ml; or

(c) a plasma AUC₀₋₂₄ of at least about 401.5±292.2 hr·ng/ml.

The present invention further provides for methods for treating at leastone central nervous system (CNS) disorder in a human subject in needthereof, comprising co-administering to the subject a pharmaceuticalcomposition comprising an effective amount of bifeprunox, a crystallinepolymorph of7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate and at least one pharmaceutically acceptableexcipient, and at least one other pharmaceutically active agent, whereinthe effective amount of bifeprunox comprises a maintenance treatmentdose.

The at least one pharmaceutically active agent other than bifeprunoxthat can be used includes, but is not limited to, CYP2C9 inhibitors,CYP3A4 inhibitors, CYP2A4 inhibitors, CYP3A4 inducers, and anypharmacologically acceptable combination thereof. Further for example,the at least one pharmaceutically active agent can include, but is notlimited to, fluconazole, ketoconazole, paroxetine, carbamazepine,warfarin, lithium, prothrombin, famotidine, and any pharmacologicallyacceptable combination thereof. Those of skill in the art are familiarwith examples of the techniques for incorporating additional activeagents for co-administration. Such additional pharmaceutically activeagents can be provided in a separate formulation and co-administered toa subject with a formulation according to the present invention. Suchseparate formulations can be administered before, after, orsimultaneously with the administration of compositions of the presentinvention. Moreover, any of the pharmaceutical compositions and dosageforms such as the maintenance treatment dose described herein canfurther comprise at least one pharmaceutically active agent other thanbifeprunox. Those of skill in the art are familiar with examples of thetechniques for incorporating additional active agents into compositionscomprising bifeprunox.

U.S. patent application Ser. Nos. 10/920,361 and 10/920,386 are herebyincorporated herein by reference in their entireties. All data hereinare understood to be approximate and subject to normal measurement errordepending, for example, on the apparatus used and other parametersinfluencing peak positions and peak intensities. Unless specificallydefined otherwise or unless the context demands otherwise, the word“about” as used herein generally means±5% of the recited value.

EXAMPLES

The following examples are only intended to further illustrate thepresent disclosure, in more detail, and therefore these examples are notdeemed to restrict the scope of the present disclosure in any way.

Example 1 Preparation of Bifeprunox Mesylate Example 1a Preparation ofN-(5-chloro-2-hydroxyphenyl)acetamide

143.6 g (1 mole) of 2-amino-4-chlorphenol was suspended in 550 ml ofmethyl t-butyl ether under mild nitrogen purge. The mixture was heatedto reflux until the material was dissolved. After 40 minutes, 112.3 g ofacetic anhydride was added. After the addition the mixture was cooled to

20-25° C. in one hour. After stirring for an additional hour the mixturewas cooled to 0-5° C. under stirring and kept on this temperature for anadditional hour. The product was filtered off, washed with 200 ml ofmethyl t-butyl ether twice and dried at 50° C. and 100 mbar under agentle nitrogen stream till dry. Yield about 92%.

Example 1b Preparation of N-(5-chloro-2-hydroxy-3-nitrophenyl)acetamide

224.5 g of sulphuric acid (50% w/w) was dissolved in 300 ml of water andcooled to 25° C. while stirring under a mild nitrogen purge. 185.1 g (1mole) of N-(5-chloro-2-hydroxyphenyl)acetamide prepared according toExample 1a was added to the diluted sulphuric acid and mixedintensively. 4 ml of nitric acid 65% w/w was added to the foam formed ontop of the reaction mixture at low stirring speed. The stirring speedwas increased and 75 ml of nitric acid 65% w/w was added in 45 minutes,while maintaining the temperature between 23 and 26° C. The mixture wasstirred vigorously for an additional

1 hour at 23-26° C. Then the mixture was cooled to 0-5° C. andvigorously stirred at this temperature for 1 hour. The solid wasfiltered off quickly, washed three times with 300 ml of cold water,sucked for at least 30 minutes and dried at 50° C. and 100 mbar under agentle nitrogen stream till dry.

The crude product was suspended in 2000 ml 96% ethanol, heated tillreflux and refluxed under stirring for about 15 minutes until a clearsolution was obtained. The solution was cooled to 25-30° C. in about 1hour, while stirring slowly, further cooled to 0-5° C. and stirred atthis temperature for an additional hour. The solid was filtered off,washed twice with 250 ml of cold 96% ethanol, and dried at 50° C. and100 mbar under a gentle nitrogen stream till dry. Yield about 78%.

Example 1c Preparation of 6-amino-4-chloro-2-nitrophenol

230.6 g (1 mole) of N-(5-chloro-2-hydroxy-3-nitrophenyl)acetamideprepared according to Example 1b was suspended in a mixture of 950 ml ofwater and 100 ml of 2-propanol under a mild nitrogen purge. 345 ml of36% w/w hydrochloric acid was added followed by 25 ml of water. Themixture was heated to reflux in about 30° C., while vigorously stirringand refluxed for 2 hours. The mixture was cooled to 0-5° C. in about onehour and stirred for an additional hour at 0-5° C. The solid wasfiltered off, washed twice with 250 ml of water, and dried at 50° C. and100 mbar under a gentle nitrogen stream till dry. Yield about 91%.

Example 1d Preparation of 5-chloro-7-nitro-2(3H)-benzoxazolone

188.6 g (1 mole) of 6-amino-4-chloro-2-nitrophenol prepared according toExample 1c was suspended in 1000 ml of ethyl acetate under mild nitrogenpurge and the optional present water was removed by azeotropicdistillation of 250 ml of the solvent. The mixture was cooled to 20-25°C. and

224 g of carbonyldiimidazole was added as a slurry in 650 ml of ethylacetate. An additional 100 ml of ethyl acetate was added and the mixturewas vigorously stirred during two hours, without the application ofcooling. 1000 ml of water was added and the mixture was stirred for 15minutes. 1450-1500 ml of ethyl acetate was distilled off at about 200mBar and about 50° C. The mixture was cooled to 0-5° C., 225 ml of 36%HCl was added and the mixture was cooled again to 0-5° C. and stirred atthis temperature for 15 minutes. The solid was filtered off, washed with400 ml of 1N HCl, washed twice with 500 ml of cold water and once with500 ml of cold water/ethanol (4/1), and dried at 50° C. and 100 mbarunder a gentle nitrogen stream till dry. Yield about 99%.

Example 1e Preparation of 7-amino-2(3H)-benzoxazolone

107.5 g (1 mole) of 5-chloro-7-nitro-2(3H)-benzoxazolone preparedaccording to Example 1d was suspended in 1000 ml of ethanol. 9.25 g ofPd/C₅% and 50 ml of ethanol were added and the mixture was hydrogenatedat 4 bar hydrogen pressure for four to six hours at 60-65° C. whilevigorously stirring. When the hydrogenation was complete, the mixturewas cooled to 45° C. and filtered over Hyflo®. The Hyflo® was washedtwice with 175 ml of methanol. 500 ml of solvent was distilled off underreduced pressure at 50° C., followed by addition of 250 ml of water andremoval of 300 ml of solvent was by distillation under reduced pressureat 50° C. The last procedure was repeated twice and finally 250 ml ofwater was added and 400 ml of solvent was distilled off. The resultingmixture was cooled to 0-5° C. in about one hour. The solid was filteredoff, washed three times with 125 ml of cold water, and dried at 50° C.and

100 mbar under a gentle nitrogen stream till dry. Yield about 94%.

Example 1f Preparation of3-[[bis(2-hydroxyethyl)amino]methyl]-1,1′-biphenyl

A mixture was prepared of 123.4 g of diethanolamine, 100 ml of water and100 ml of methylethylketone (MEK) and 500 ml of methyl t-butyl etherwhile stirring under a mild nitrogen purge 124.75 g of3-(bromomethyl)-1,1′-biphenyl was added together with 750 ml of methylt-butyl ether. The mixture was heated to reflux and refluxed for 18hours, followed by cooling till room temperature. Thereafter the mixturewas washed once with 375 ml of 2N NaOH and four times with 375 ml ofwater. The combined 2N NaOH and water layers were extracted with 750 mlof methyl t-butyl ether. The combined methyl t-butyl ether layers werewashed with 250 ml of water followed by distillation of as much methylt-butyl ether as possible from the organic layer. 1350 ml ofmethylethylketone was added and 600 ml of solvent was distilled of atatmospheric pressure. The solution was cooled to room temperature andstored for use in the next step. Yield based on quantitative assay 97%.

Example 1g Preparation of Bifeprunox Mesylate (Crude)

A solution of 128.9 g of3-[[bis(2-hydroxyethyl)amino]methyl]-1,1′-biphenyl in approximately 750ml of methylethylketone prepared according to Example 1f was stirredunder mild nitrogen purge. In a separate vessel 202 g of methanesulfonicanhydride was dissolved in 600 ml of methylethylketone at

10-20° C. To the solution of3-[[bis(2-hydroxyethyl)amino]methyl]-1,1-biphenyl in methylethylketone212.8 g of triethylamine was added and 60 ml of methylethylketone. Thesolution of methanesulfonic anhydride was added in about 45-60 minutesto the 3-[[bis(2-hydroxyethyl)amino]methyl]-1,1′-biphenyl/triethylaminesolution, while maintaining the temperature below 10° C. 60 ml ofmethylethylketone was added and the mixture was stirred for another15 minutes, followed by drop wise addition of 109.7 g of methanesulfonicacid and addition of 60 ml of methylethylketone in order to rinse theaddition vessel.

71.3 g of 7-amino-2(3H)-benzoxazolone, prepared according to Example 1ewas suspended in 100 ml of methylethylketone and added to the reactionmixture followed by 60 ml of methylethylketone. The reaction mixture washeated to reflux and refluxed for 20-24 hours. After 20-24 hours ofreflux

48 ml of water was added and the mixture was refluxed again for 1 hour.420 ml of methylethylketone was added and 490 ml ofmethylethylketone/water was distilled of. This last step was repeatedthree times. 46.1 g of methanesulphonic acid was added, the mixture wasrefluxed for an additional hour and cooled down to room temperature in 1hour. The mixture was further cooled down to 0-5° C. and stirred at thistemperature for another hour. The solid was filtered off and, washedtwice with 75 ml of cold methylethylketone, and dried at 50° C. and100 mbar under a gentle nitrogen stream till dry. Yield about 76%.

Example 2 Preparation of Polymorphic Form α of Bifeprunox Mesylate in2-Propanol

10.06 g of bifeprunox mesylate crude prepared as described Example 1gwas suspended in a mixture of 200 ml of 2-propanol and 40 ml of waterunder nitrogen purge. The suspension was heated until reflux and cooleddown to room temperature in 120 minutes under stirring. The formedsuspension was further cooled down under stirring to 0° C. and stirredat this temperature for a further 120 minutes. The crystals werefiltered of and dried at 50° C. and 100 mbar.

Example 3 Preparation of Polymorphic Form α of Bifeprunox Mesylate inAcetonitrile

50 g of bifeprunox mesylate prepared crude as described in Example 1gwas suspended in a mixture of 875 ml of acetonitrile and 250 ml of waterunder nitrogen purge. 375 ml of acetonitrile was added and the reactionmixture was heated till reflux. 500 ml of solvent was distilled off and500 ml of acetonitrile were added and this procedure was repeated for asecond time. After distilling another 500 ml of solvent the mixture wascooled down to room temperature in 120 minutes. The mixture was furthercooled down to 0-5° C. and stirred for 120 minutes at this temperature.The formed crystals were filtered off and washed twice withacetonitrile. The isolated crystals were dried at 50° C. and 100 mbarunder a mild nitrogen purge. Yield 85.6%.

Example 4 Preparation of Polymorphic Form γ of Bifeprunox Mesylate

To a suspension of 12.50 g of bifeprunox mesylate (crude) prepared asdescribed in Example 1g in 150 ml of methylethylketone (MEK)

75 ml of a 5% NaHCO₃ solution was added in about 10-15 min. After5-10 minutes of stirring the suspension was filtered over Hyflo® orCelite® into another vessel where the layers were separated. The waterlayer was extracted with 125 and 75 ml of methylethylketone. Themethylethylketone layers were combined and washed with a mixture of 50ml of water and 10 ml of ethanol 96%.

The methylethylketone layer was filtered through a 1 μm filter into aclean vessel, after which the filter was rinsed with 25 ml ofmethylethylketone. Methylethylketone was distilled off until a volume ofabout 130 ml was reached, 200 ml of methylethylketone was added andagain methylethylketone was distilled off to reach a volume of 175 ml.

Next, a solution of 3.00 grams of methane sulphonic acid in 50 ml ofmethylethylketone was added in about 30 min. After cooling to 5° C. andstirring for 1½ hours at this temperature the product was filtered offand washed twice with 50 ml of cold methylethylketone. After drying at50° C. and 100 mbar under a mild nitrogen purge the gamma (γ) polymorphof bifeprunox mesylate yield was about 80%.

Example 5 Preparation of a 10 mg Capsule Formulation of Polymorphic Formα of Bifeprunox Mesylate

2.227 kg of lactose was sieved and filled into a high shear mixer. 125 gof bifeprunox mesylate in its polymorphic form α was sieved and added.The composition was mixed with a high shear mixer (e.g. Collette Gral 10or Collette Gral 75) until it was homogenous (approximately 4 minutes).24 g of a disintegrant (e.g. sodium starch glycolate USP-NF such asPrimojel®) and 24 g of a lubricant (e.g. sodium stearyl fumarate such asPRUV®) were added and the composition was mixed again until it washomogenous (approximately 1 minute). The powder was filled into capsulessize 0, 240 mg per capsule by means of a capsule filling machine (e.g.Zanasi LZ 64 or Zanasi RM63 plug filler). Approximately 10,000 filledcapsules were obtained.

Example 6 Preparation of a 10 mg Tablet Formulation of BifeprunoxMesylate Polymorphic Form α

Tablets with a strength of 10 mg were prepared according to thefollowing procedures (required quantities are given in Table 8). Onethird of the given amount of lactose monohydrate was sieved and filledinto a high shear mixer and mixed during 5 minutes. The required amountof milled bifeprunox mesylate in its polymorphic form a was added to themixture, together with

0.100 kg sodium starch glycolate, type A, 2.32 kg microcrystallinecellulose and the remainder of the lactose monohydrate. The compositionwas mixed with a high shear mixer (e.g. Collette Gral 10 or ColletteGral 75) until it was homogenous (approximately 10 minutes). Therequired amount of a sodium stearyl fumarate (such as PRUV®), sievedthrough a 0.42 mm sieve was added and the composition was mixed againuntil it was homogenous (approximately5 minutes). The final product was compressed with 300 MPa into tablets.The product was coated using 15% m/m of the indicated Opadry II HP watersuspension to 3.5% of the core weight.

Table 8 shows the amount of active ingredient and auxiliary materialsused in a large scale production of 10 mg bifeprunox mesylate tablets.

TABLE 8 Per batch of 83333 10 mg tablets Components (in kg) Corecomponents Bifeprunox mesylate (milled) 1.041 Lactose monohydrate 16.33Microcrystalline cellulose 2.32 Sodium starch glycolate, type A 0.100Sodium stearyl fumarate 0.200 Coating components Opadry II HP beige85F27126 0.700 Purified water 3.968

Example 7 Analytical Methods

XRPD patterns were measured on a diffractometer using monochromatic CuKaradiation (tube voltage 40 kV, tube current 40 mA) at room temperature.IR spectra were recorded on a Fourier transform IR spectrometer inattenuated total reflectance (silicon crystal) with a spectralresolution of 2 cm⁻¹ using a mercury cadmium telluride detector.

Melting points were determined on a DSC apparatus as onset temperaturesof the melting endotherm using 40 μL aluminum crucibles with a piercedlid. Temperature program: heating from 25° C. up to 300° C. with 10 Kmin⁻¹. N₂ atmosphere at a flow of 80 mL min⁻¹.

The solid state ¹³C NMR spectra were obtained using thecross-polarisation magic-angle spinning (CP/MAS) accessory on a BrukerAM300 instrument (contact time of 4 ms, recycle delay 3 s, spectralwidth 30 kHz,

¹H 90° pulse of 6 μs, spinning rate about 8.5 kHz. A standard 4 mmBruker CP/MAS probe was used. Chemical shifts are referred to glycine(δ_(c)=176.03 ppm for the C═O resonance).

Crystals of the alpha (α) form appeared under the microscope asblock-shaped, those of the gamma (γ) crystal form were plate- orrod-shaped, whereas crystals of the delta (δ) crystal form lookedblock-shaped with rounded edges.

For each crystal form, a crystal was transferred into the cold nitrogenstream on a rotating anode X-ray diffractometer. The structures weresolved by automated direct methods. Hydrogen atoms bonded to nitrogenwere located on an electron-density map and their coordinates wereincluded as parameters in the refinement. Other hydrogen atoms wereincluded in the refinement on calculated positions riding on theircarrier atoms. All non-hydrogen atoms were refined with anisotropicatomic displacement parameters. Hydrogen atoms were given fixeddisplacement factors, related to those of their carrier atoms.

Example 8 Pharmacokinetic Study

A single center, open label, randomized, double two-way cross-over studywas used to assess the relative bioavailability of a 0.125 mg and a 20mg (active ingredient amount) capsule formulation (δ polymorphic form ofbifeprunox mesylate) respectively with a 0.125 mg and 20 mg (activeingredient amount) tablet formulation of the α polymorphic form ofbifeprunox mesylate after oral administration to healthy male and femalevolunteers. Capsules and tablets were prepared substantially asdescribed in Examples 5 and 6 with appropriate adjustments for dose andformulation, e.g., capsules or tablets.

Treatment started with a single dose of 0.125 mg bifeprunox mesylate aseither a capsule or tablet formulation. The first cross-over started onDay 3 when a single dose of 0.125 mg bifeprunox mesylate, in theopposite formulation than that started with, was given. Next, after onedrug free day, the subjects were uptitrated with the Day 3 formulationover a period of 8 days

(Days 5-12). Subsequently, the 20 mg formulation was given for anadditional 3 days (Days 13-15), followed by a second cross-over to a 20mg treatment of the first formulation (capsule or tablet) for four days(Days 16-19).

Pharmacokinetic parameters were determined two times for 48 hoursstarting on Days 1 and 3 (for the single dose pharmacokinetics), and twotimes for 24 hours starting on Days 15 and 19 (for multiple dosepharmacokinetics). For differences between the test (tablet) and thereference (capsule) treatment, 90% confidence intervals are given forthe 0.125 mg and

20 mg treatments. The information for the 0.125 data is extracted out ofthe Day 1 and Day 3 measurements, while the steady state plasma levelsof Day 15 and Day 19 are used for the pharmacokinetic information of the20 mg regimen.

Pharmacokinetic results are shown in Table 9.

TABLE 9 AUC_(0-t) AUC₀₋₂₄ AUC Dose T_(max) C_(max) (hr · (hr · (hr ·(mg) Formulation (hr) (ng/ml) ng/ml) ng/ml) ng/ml) 0.125 Capsule (δ)3.16 0.155 0.904 — 1.31 0.125 Tablet (α) 2.31 0.281 1.46  — 1.69 20Capsule (δ) 2.00 50.8 — 352 — 20 Tablet (α) 1.81 54.1 — 349 —

As is shown above, the bioavalability (AUC, C_(max)) of the 0.125 mgtablet was higher compared to the reference capsule. Compared to thecapsule, that tablet also exhibited a faster T_(max). From 6 hours postadministration up to the last measurable plasma concentrations, theaverage plasma concentration time profiles were nearly congruent forboth formulations.

Following multiple 20 mg doses, no major differences were found betweenthe capsule and tablet formulation. For the AUC, the 90% confidenceintervals of the ratio tablet/capsule were within the 80%-125% range.

Example 9 Tablet Dissolution

Three different strengths of tablets (10 mg, 5 mg and 1 mg of bifeprunoxmesylate) were prepared having the compositions shown in Table 10; thetablets were designated T1, T2 and T3, respectively.

TABLE 10 T1 T2 T3 Label claim, mg/tablet 10.0 5.0 1.0 Component Quantity(mg) Bifeprunox 12.49 6.25 1.25 Lactose monohydrate 3.75 4.50 3.60Lactose monohydrate ¹ 106.26 136.25 112.75 Sodium starch glycolate 1.251.50 1.20 Sodium stearyl fumarate 1.25 1.50 1.20 ¹ Direct Compression

Each of the tablets were placed in a dissolution test under thefollowing conditions: Apparatus: paddle method; Stirring speed: 50 rpm;Amount of test dissolution medium: 900 ml; Temperature of dissolutionmedium:

37° C.±0.5° C.

Six different dissolution media were used as follows:

Media 1: Dissolve 2.0 g of sodium chloride dissolved in 7.0 ml ofhydrochloric acid, q.s. with water to make 1000 ml (pH 1.2);

Media 2: MclLvaine buffer solution (pH 3.0), pH adjusted with 0.05 mol/Lof sodium hydrogen phosphate and 0.025 mol/L of citric acid;

Media 3: MclLvaine buffer solution (pH 4.0);

Media 4: MclLvaine buffer solution (pH 5.0);

Media 5: Water;

Media 6: To 250 ml of 0.2 mol/L potassium dihydrogenphosphate TS add 118ml of 0.2 mol/L sodium hydroxide TS and water to make 1000 ml.

Tables 11-16 show dissolution results in each of the above media,respectively. Dissolution testing was performed in triplicate.

TABLE 11 Media 1 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 <LOD <LOD <LOD <LOD<LOD <LOD <LOD <LOD <LOD 60 24.1 24.4 23.7 24.0 22.5 14.6 14.0 13.1 1.5120 26.1 26.5 25.9 26.3 24.9 18.2 17.6 16.7 1.8 180 27.1 27.5 27.1 27.526.2 20.1 19.6 18.8 2.1 240 27.9 28.1 27.9 28.4 27.0 21.5 20.9 20.2 2.3300 28.4 28.7 28.4 28.9 27.4 22.4 21.9 21.3 2.5

TABLE 12 Media 2 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 <LOD <LOD <LOD <LOD<LOD <LOD <LOD <LOD <LOD 6 68.7 70.4 78.2 70.2 69.0 78.7 99.3 96.4 94.912 95.3 91.6 94.6 93.6 92.9 94.5 103.6 102.0 102.8 20 99.2 97.1 97.497.8 99.6 97.9 106.5 104.8 103.2 30 100.3 97.7 98.5 99.6 101.6 98.0106.1 105.5 104.1 45 101.1 99.1 97.9 100.3 102.5 98.2 107.6 107.3 104.360 100.9 100.2 99.2 99.8 102.6 98.7 107.0 106.7 104.7

TABLE 13 Media 3 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 0.2 0.2 0.2 0.2 0.2 0.20.2 0.2 0.2 6 59.9 58.8 65.0 33.9 36.2 33.1 47.1 52.0 57.7 12 80.2 79.884.6 50.5 50.6 50.3 67.7 69.6 79.0 20 90.1 92.9 91.0 67.0 64.2 66.5 89.482.5 84.1 30 92.3 96.5 93.1 75.1 74.8 74.1 91.3 90.4 89.8 45 95.2 98.895.1 82.6 82.4 82.9 97.4 94.8 96.0 60 96.5 98.9 94.9 86.4 86.5 86.8 97.196.5 96.6

TABLE 14 Media 4 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 <LOD <LOD <LOD <LOD<LOD <LOD <LOD <LOD <LOD 60 34.9 38.0 34.4 41.7 32.6 37.6 35.6 22.6 25.4120 46.5 34.1 47.4 46.9 43.6 38.5 41.0 41.6 37.0 180 39.6 39.4 45.8 33.444.1 41.1 39.2 43.5 34.2 240 38.8 45.5 43.0 45.6 50.8 49.0 44.0 50.936.9 300 47.1 34.0 40.5 57.1 42.3 37.1 53.7 50.6 58.1

TABLE 15 Media 5 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 <LOD <LOD <LOD <LOD<LOD <LOD <LOD <LOD <LOD 6 65.3 64.9 71.6 73.6 72.3 60.4 70.8 84.9 77.112 82.8 88.5 91.0 86.7 86.4 87.9 92.7 89.5 96.8 20 89.9 95.9 96.0 91.190.2 94.7 97.1 97.8 102.2 30 91.3 97.0 97.2 92.5 91.2 97.1 100.4 98.6105.7 45 92.0 97.8 97.7 93.0 91.2 98.7 101.6 100.5 106.4 60 91.9 98.097.8 92.7 91.1 99.6 102.5 101.1 107.8

TABLE 16 Media 6 10 × 1.0 mg tablets 2 × 5.0 mg tablets 1 × 10.0 mgtablets % RLC dissolved bifeprunox % RLC dissolved bifeprunox % RLCdissolved bifeprunox Time in Vessel Vessel Vessel Vessel Vessel VesselVessel Vessel Vessel minutes 1 2 3 1 2 3 1 2 3 0 <LOD <LOD <LOD <LOD<LOD <LOD <LOD <LOD <LOD 60 6.9 8.2 7.9 7.1 4.1 <LOD <LOD <LOD <LOD 1206.6 8.3 7.2 7.7 5.4 <LOD <LOD <LOD <LOD 180 7.1 10.3  7.5 7.6 5.2 <LOD<LOD <LOD <LOD 240 9.9 9.2 7.8 8.0 7.3 <LOD <LOD <LOD <LOD 300 7.5 9.18.0 8.3 7.6 <LOD <LOD <LOD <LOD

As can be seen in the above tables, there is no difference indissolution behavior between 1.0 mg, 5.0 mg and 10.0 mg tablets ofbifeprunox. Bifeprunox dissolves almost immediately in MclLvaine bufferpH 3.0.

It is believed that the difference in dissolved bifeprunox in Table 11between 1.0 mg, 5.0 mg and 10.0 mg tablets is caused by the differentamounts of excipients, e.g. 10 tablets of 1.0 mg, 2 tablets of 5.0 mgand 1 tablet of 10.0 mg in the dissolution vessels. Some of theexcipients are surface active.

Overall, the dissolution behavior of tablets with the strengths of 1.0mg, 5.0 mg and 10.0 mg bifeprunox are substantially the same.

Example 10 Clinical Studies of Bifeprunox Using Maintenance Doses

The pharmacokinetics of bifeprunox in healthy subjects were investigatedbased on a pooled analysis of pharmacokinetic (PK) parameters from 21clinical pharmacology studies. The pooled analysis included PK profilesobtained following single and multiple doses administered to 132 and 399subjects, respectively, and explored the potential effects of age,gender, body weight and race. In addition, PK in patients (PTS) withschizophrenia were investigated using a population PK approach based onsamples from 376 subjects in phase II studies and 434 subjects in phaseIII studies.

In healthy subjects and patients with schizophrenia, the maximumtolerated single dose of bifeprunox was 0.5 mg. Tolerance todose-limiting side effects (nausea, dizziness, vomiting, and orthostatichypotension) developed as the dosage was titrated upwards. All PKassessments at doses higher than 0.5 mg were performed followingmultiple dosages under steady-state conditions. Doses of 5-40 mg wereadministered in efficacy studies. PK parameters describing absorption,distribution, metabolism, and elimination were calculated based onnon-compartmental analysis. PK parameter values from each study werecombined to create a pooled dataset. The potential influence of gender,body weight, and race on bifeprunox PK was analyzed.

Bifeprunox PK parameters following multiple dose administration areshown in Table 17.

TABLE 17 Dose *C_(max) *AUC₀₋₂₄ V_(Zbw)/F CL_(bw)/F (mg/day) (ng/mL) (ng· hr/mL) T_(max) (h) T_(1/2) (h) (L/kg) (L/h/kg) N 334 334 334 196 196335 20 and 40 62.1 ± 38.2 401.5 ± 292.2 2.0 (0.5-8.0) 14.4 ± 5.3 17.3 ±9.4 0.9 ± 0.3 mg/day V_(Zbw)/F = apparent volume of distributioncorrected by body weight. CL_(bw)/F = weight normalized oral clearance.Data presented as mean ± SD for all parameters except T_(max), which ispresented as median (range) *Dose normalized to 20 mg.

Absorption

Bifeprunox was rapidly absorbed after oral administration. The mediantime to peak plasma concentration (T_(max)) was approximately 2 hours.See FIG. 16. Multiple patients were dosed proportional in the 20 to 40mg/day range (mean AUC₀₋₂₄ for 20 mg: 381.5 ng·hr/mL and mean AUC₀₋₂₄for 40 mg: 825.1 ng·hr/mL). Administration with a high-fat meal wasstudied at the 40 mg dose, and appeared to have a minimal impact:T_(max) was delayed by 1.5 hours and C_(max) (maximum observed plasmaconcentration-time curve over the dosing interval of 24 hours) increasedby 29%. Moreover, it was demonstrated that bifeprunox can beadministered with or without food. Bioavailability was predicted to be54% based on hepatic blood flow and oral clearance. Absolute oralbioavailability of the bifeprunox tablets used in the pooled studies hasnot been determined.

Distribution

Apparent volume of distribution (Vz/F) was 1300 L. Based upon the volumeof distribution, bifeprunox was extensively distributed into theperipheral tissues. No extensive distribution of bifeprunox or itsmetabolites into red blood cells occurred. Bifeprunox was more than 99%bound to plasma proteins in healthy patients as well as those with renalor hepatic impairment. The blood/plasma ratio for bifeprunox wasobserved to be in the range of 0.7 to 0.9.

Metabolism

Based on in vitro data, bifeprunox was metabolized in the liverprimarily by the CYP2C9 and CYP3A4 enzymes, with minor contribution fromCYP2A4. Among healthy subjects with reduced enzyme activity for CYP2C((intermediates/slow metabolizers), bifeprunox C_(max) were 3.1 to 3.9fold, respectively, higher than for extensive metabolizers. Likewise,AUC values were, respectively, 3.7 and 7.1-fold higher for intermediateand slow metabolizers, than for extensive metabolizers.

Elimination

Steady-state mean oral clearance (CL/F) was 62.2 L/h. The meansteady-state elimination half-life (t_(1/2)) following multiple doseadministration was 14.4 hours. Steady-state levels were reached within 2to 4 days. Administration of a single-dose of [¹⁴C]-labeled bifeprunox(0.25 mg) showed that 13% of radioactivity was excreted via the urine,and 73% via the feces. Overall, 89% of radioactivity was excreted. Theamounts of unchanged bifeprunox excreted in the urine and feces were 2%and 17%, respectively.

Effects of Age, Gender, Body Weight and Race

Pooled analysis showed no clinically relevant age-, gender-, bodyweight-, or race-related effects on bifeprunox PK.

Drug-Drug Interactions

Co-administration with the potent CYP2C9 inhibitor and weak CYP3A4inhibitor, fluconazole increased mean bifeprunox C_(max) and AUC₀₋₂₄ by2.5- and 3.7-fold, respectively. See FIG. 17B. The CYP3A4 inhibitorketoconazole increased bifeprunox C_(max) and AUC₀₋₂₄ by 44% and 63%,respectively. See FIG. 17A. Co-administration with CYP2A4 inhibitorparoxetine had no effect on bifeprunox PK. See FIG. 17C. Bifeprunoxexposure was reduced by approximately 50% after co-administration withthe CYP3A4 inducer carbamazepine. See FIG. 17D. Carbamazepine decreasedmean C_(max) and AUC₀₋₂₄ by 50% and 54%, respectively. Bifeprunox had noeffect on the PK and pharmacodynamics of warfarin and the PK of lithium.The prothrombin time profile as a function of study day followingtreatment with warfarin was comparable in the presence and absence ofbifeprunox. See FIG. 18.

Administration of famotidine, an H2 antagonist that inhibits gastricacid secretion, had no effect on bifeprunox PK.

PK in Patients

A population-based PK assessment using compartmental methods wasconducted in 810 patients with schizophrenia enrolled in severalclinical studies. Bifeprunox PK were similar in healthy subjects (HS)and schizophrenia patients (SP): bifeprunox Vz/F was approximately 1300L in HS versus 1100 L in SP; bifeprunox Cl/F was 62.2 L/hr in HS versus57 L/hr in SP; and bifeprunox t_(1/2) was 14 hrs in HS versus 15 hrs inSP.

Based on those pharmacokinetics, bifeprunox (an investigational partialdopamine agonist antipsychotic compound) was rapidly absorbed after oraladministration. Multiple-dose PK of bifeprunox were dose proportionalover the range of 20 to 40 mg doses. Bifeprunox was extensivelydistributed into peripheral tissues and highly protein bound. It wasprimarily eliminated in the feces. Based on in vivo data, bifeprunox wasprimarily metabolized by CYP2C9 and to a lesser extent by CYP3A4.Bifeprunox was eliminated from the systemic circulation with asteady-state elimination t_(1/2) of approximately 14 hours; steady-statewas reached within 2 to 4 days. Bifeprunox has a low drug interactionpotential with other drugs used in these studies (e.g. lithium, warfarinand famotidine).

1-34. (canceled)
 35. A method of treating at least one central nervoussystem (CNS) disorder in a human patient in need thereof, comprisingco-administering to the patient a pharmaceutical composition comprisingan effective amount of bifeprunox, a crystalline polymorph of7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolonemonomethanesulfonate and at least one pharmaceutically acceptableexcipient, and at least one other pharmaceutically active agent, whereinthe effective amount of bifeprunox comprises a maintenance treatmentdose.
 36. The method according to claim 35, wherein the at least oneother pharmaceutically active agent is chosen from CYP2C9 inhibitors,CYP3A4 inhibitors, CYP2A4 inhibitors, CYP3A4 inducers, and anypharmacologically acceptable combination thereof.
 37. The methodaccording to claim 35, wherein the at least one other pharmaceuticallyactive agent is chosen from fluconazole, ketoconazole, paroxetine,carbamazepine, warfarin, lithium, prothrombin, famotidine, and anypharmacologically acceptable combination thereof.